The hypothalamus-pituitary-adrenal (interrenal) axis HPA(l)J is a neuroendocrine network responsible for modulating a broad range of physiological functions from reproductive activity to chronic stress response. Within this network, corticotropic cells in the anterior lobe of the pituitary express proopiomelanocortin (POMC), a precursor protein from which the polypeptide hormone, adrenocorticotropin (ACTH), is post-translationally released. ACTH is well established as a critical link in this network. Neurons in the hypothalamus secrete corticotropin releasing hormone (CRH), which induces the secretion of ACTH from the anterior pituitary. ACTH, in turn, stimulates the adrenal gland to synthesize and release cortisol, which is the final hormone in the chronic stress response cascade. Fluctuations in the production and/or regulation of CRF, ACTH or cortisol can have serious consequences with respect to the survival of an organism. Hyposecretion of cortisol results in Addison's Disease. Conversely, hypersecretion of cortisol is associated with Cushing's Syndrome, a multi-symptom metabolic disorder characterized by muscle atrophy, immune deficiency, adrenal hyperplasia, kidney dysfunction and general tissue degeneration. In contrast to humans, where the U.S. frequency of Cushing's Syndrome is on the order of 3700 cases annually, 100 percent of Pacific salmon display Cushing's Syndrome-like tissue and organ degeneration coincident with spawning. While it had been thought that the stress of marine to freshwater migration was responsible for the post-spawning demise of these fish, studies have now implicated overproduction of cortisol during sexual maturation as the factor which ultimately leads to the demise of spawning salmon. The current proposal will use a combination of cell and molecular strategies to investigate the role of P0MG and hypothalamic neuropeptides (CRH, AVT and Uro I) in the regulation of the HPA axis. This wilt help to identify specific components of HPA(I) axis which are altered during the sexual maturation of Pacific salmon, and which lead to their inevitable post-spawning demise. An understanding of the molecular mechanisms underlying the development of Cushing's Syndrome-like pathology in Pacific Salmonids has the potential not only to advance our knowledge of the role of the HPA(I) in reproductive stress, but to contribute to a broader understanding of the etiology and pathogenesis of hypercorticism in humans.